An asymmetric synthetic method for (1R,2S,3R)-1-((R)-epoxyethylene-2-yl)-4-penten-1,3-diol

Abstract

This invention discloses an asymmetric synthesis method for (1R,2S,3R)-1-((R)-ethyleneoxy-2-yl)-4-penten-1,3-diol. The epoxide compound is prepared by catalytic oxidation in an organic solvent at 10–25°C using a 1,6-heptadien-3,5-diol compound with a fourth-position substitution as the starting material. The molar ratio of the catalytic oxidation starting material, catalyst, and oxidant is 1:0.01–0.06:1.0–2.0. The catalyst is one or a combination of two of Berkessel-Katsuki and Nitro-Salalen-Ti, and the oxidant is a peroxide. In this invention, by using a symmetrical 1,6-heptadien-3,5-diol compound as the starting material and selectively oxidizing one of the double bonds, the epoxide compound is constructed, achieving desymmetry of the meso compound.

Description

Technical Field

[0001] This invention relates to a method for synthesizing organic compounds, and particularly to an asymmetric method for synthesizing (1R,2S,3R)-1-((R)-epoxyethylene-2-yl)-4-penten-1,3-diol. Background Technology

[0002] Polyhydroxy compounds containing continuous chiral centers are widely found in natural products, bioactive molecules, and drugs, such as migalastat (Galafold), a drug used to treat Fabry disease, a genetic disorder; D-glycerol-D-mannose-heptanose, which has antibacterial activity; and polyhydroxyperhydrozepines or seven-membered imine cyclic alcohols, which inhibit glycosidases and glycosyltransferases. The synthetic research of compounds containing continuous chiral centers is of great significance.

[0003]

[0004] Due to ring strain, epoxides are much more reactive than ordinary ethers, readily undergoing ring-opening reactions with a wide variety of reagents, making them very versatile synthetic intermediates. Using epoxides containing continuous chiral centers as substrates, under suitable conditions, five-membered nucleosides, hexoses, piperidines, and cycloheximines can be rapidly synthesized into drugs with antiviral, antibacterial, and enzyme inhibitor properties. Therefore, the preparation of epoxides with continuous chiral centers is fundamental to the synthesis of polyhydroxy compounds containing continuous chiral centers.

[0005] In 1980, Karl Barry Sharpless et al. first reported the asymmetric epoxidation reaction (Sharpless Epoxidation), using tetraisopropoxytitanium and diethyl tartrate as synergistic catalysts and tert-butyl hydroperoxide as the oxidant, with primary and secondary allyl alcohols as substrates to achieve the asymmetric epoxidation reaction (J. Am. Chem. Soc. 1980, 102, 5974-5976.). This reaction is often used in the kinetic resolution of racemic alcohols.

[0006]

[0007] In 2005, Katsuki et al. synthesized a dimer-Ti-trans-DACH salalen catalyst, using hydrogen peroxide as an oxidant, to catalyze the asymmetric epoxidation of non-conjugated terminal olefins. It showed high yields and good enantioselectivity for various types of substrates (Angew. Chem. Int. Ed. 2005, 44, 4935.).

[0008]

[0009] In 2013, Berkessel et al. optimized and designed a novel Salalen catalyst, which showed high yields and excellent enantioselectivity in the asymmetric epoxidation of non-conjugated terminal olefins (ChemCatChem, 2016, 8, 3706–3709.).

[0010]

[0011] In 2023, Berkessel's group reported a newly improved NO2-Salalen catalyst, which further enhanced the activity and stereocontrol of epoxidation catalysts. In the asymmetric epoxidation of non-conjugated terminal olefins, epoxidized products were obtained with low catalyst amounts, high yields, and excellent enantioselectivity (Angew. Chem. Int. Ed., 2023, 62, e202306584.).

[0012] Summary of the Invention

[0013] Purpose of the invention: The purpose of this invention is to provide a method for synthesizing asymmetric (1R,2S,3R)-1-((R)-epoxyethylene-2-yl)-4-penten-1,3-diol by selective oxidation of a single double bond.

[0014] Technical Solution: The present invention discloses an asymmetric synthesis method for (1R,2S,3R)-1-((R)-ethyleneoxy-2-yl)-4-penten-1,3-diol, which uses a 1,6-heptadien-3,5-diol compound substituted at the fourth position as a raw material and a peroxide as an oxidant. The raw material is prepared by catalytic oxidation in an organic solvent at room temperature. The catalyst for the catalytic oxidation reaction is one or a combination of two of Berkessel-Katsuki and Nitro-Salalen-Ti. The molar ratio of the raw material, catalyst, and peroxide is 1:0.01-0.06:1.0-2.0.

[0015] In this invention, symmetrical 1,6-heptadien-3,5-diol compounds are used as raw materials, and one of the double bonds is selectively oxidized to construct an epoxide compound, thereby achieving the desymmetry of the meso compound.

[0016] Preferably, the catalytic oxidation reaction also includes a co-catalyst in the same amount as the catalyst, wherein the co-catalyst is one or more combinations of n-butylammonium bisulfate, benzoic acid, and 2,6-di-tert-butylpyridine. The reaction can proceed smoothly without the addition of a co-catalyst and yield the desired product; however, the addition of a co-catalyst increases the yield of the desymmetric ethylene oxide compound.

[0017] Preferably, the general formula of the substituent at position four of the raw material is: n=0~3, R=Me, Ph, OBn, oF-Ph or p-Me-Ph.

[0018] Preferably, the structure of the Berkessel-Katsuki, Nitro-Salalen-Ti catalyst is as follows:

[0019]

[0020] Preferably, the steps for synthesizing the Nitro-Salalen-Ti catalyst are as follows:

[0021] (1) Under inert gas protection, Ti(OiPr)4, chloroform solvent and Nitro-salalen ligand were added in proportion and stirred at room temperature for no less than 30 minutes. The ratio of Ti(OiPr)4 to Nitro-salalen ligand was 1:1 and the ratio of solvent was 1 mmol: 20 mL.

[0022] (2) Add water to the product obtained in step (1) in proportion and continue stirring for at least 30 minutes. The water addition ratio is 1 mmol: 40 drops.

[0023] (3) Filter out excess water from the product obtained in step (2) with anhydrous sodium sulfate, and continue to add 10 μL of hydrogen peroxide with a mass fraction of 50±5%, and stir for no less than 3 hours;

[0024] (4) Remove the solvent from the product obtained in step (3) to obtain the Nitro-Salalen-Ti catalyst.

[0025] Preferably, the step of synthesizing the Berkessel-Katsuki catalyst is as follows.

[0026] (1) Under inert gas protection, Ti(OiPr)4, chloroform solvent and salalen ligand were added in proportion and stirred at room temperature for no less than 30 minutes. The ratio of Ti(OiPr)4 to salalen ligand was 1:1 and the ratio of solvent was 1 mmol: 20 mL.

[0027] (2) Add water to the product obtained in step (1) in proportion and continue stirring for at least 30 minutes. The water addition ratio is 1 mmol: 40 drops.

[0028] (3) Filter out excess water from the product obtained in step (2) and remove the solvent to obtain the Berkessel-Katsuki catalyst.

[0029] Preferably, the molar ratio of the raw material, catalyst, and peroxide is 1:0.015-0.025:1.2-1.5, and the peroxide is an aqueous solution of hydrogen peroxide with a mass fraction of 30-60%. More preferably, the peroxide is an aqueous solution of hydrogen peroxide with a mass fraction of 40-55%.

[0030] Preferably, the organic solvent is one or a combination of dichloromethane, 1,2-dichloroethane, and chloroform.

[0031] Preferably, the catalytic oxidation reaction lasts for at least 45 hours.

[0032] Preferably, the raw material is prepared by sequentially undergoing aldol condensation, hydroxyl protection, ammonolysis, Grignard alkenylation, deprotection, and reduction reactions of acrolein and ethyl acetate with methyl hydrogen substituted.

[0033] Preferably, the catalytic oxidation reaction temperature is 10–30°C.

[0034] More preferably, the aldol condensation reaction equation and steps are as follows:

[0035]

[0036] (1) Ethyl acetate with methyl hydrogen replaced was added to the reaction system. Molecular sieve, dichloromethane, cooled to no higher than -78°C;

[0037] (2) Based on ethyl acetate with methyl hydrogen substituted, add n-BuBOTf dropwise at a molar ratio of 1:1.3 for a time of not less than 30 min, add DIEA at a molar ratio of 1:1.6 for a time of not less than 30 min, and after the addition is complete, the reaction time shall be not less than 3.5 hours.

[0038] (3) Based on ethyl acetate with methyl hydrogen substituted, add acrolein dropwise at a molar ratio of 1:5, with a dropping time of not less than 30 min and a reaction time of not less than 2 hours.

[0039] (4) Heat the product obtained in step (3) to no higher than 0°C and react for no less than 8 hours to obtain the aldol condensation product, racemic (2R*,3S*)-3-hydroxy-4-pentenoic acid ethyl ester.

[0040] More preferably, the hydroxyl protection reaction equation and steps are as follows:

[0041]

[0042] (1) Add aldol condensation product, 2,6-dimethylpyridine, and dichloromethane to the reaction system, dissolve, and cool to no higher than -78℃, wherein the molar ratio of aldol condensation product to 2,6-dimethylpyridine is 1:1.5;

[0043] (2) Based on the aldol condensation product, add TBSOTf dropwise at a molar ratio of 1:1.2 for a time of not less than 30 min. After the addition is complete, restore the temperature to room temperature and react for not less than 2 hours to obtain the hydroxyl protected product, racemic (2R*,3S*)-3-((tert-butyldimethylsilyl)oxy)-4-pentenoic acid ethyl ester.

[0044] More preferably, the ammonium hydrolysis reaction equation and steps are as follows:

[0045]

[0046] (1) Under ice-water bath conditions, hydroxyl protecting product, tetrahydrofuran, and dimethyl hydroxyl ammonium hydrochloride were added to the reaction system, wherein the molar ratio of hydroxyl protecting product to dimethyl hydroxyl ammonium hydrochloride was 1:1.5;

[0047] (2) Based on the hydroxyl protected product, add isopropyl magnesium chloride solution dropwise at a molar ratio of 1:3 for a time of not less than 30 min. After the addition is complete, restore the temperature to room temperature and react for not less than 2 hours to obtain the ammonium hydrolysis product, racemic (2R*,3S*)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methyl-4-pentenamide.

[0048] The Grignard alkenylation reaction equation and steps are as follows:

[0049]

[0050] (1) Under ice-water bath conditions, the ammonium hydrolysis product, tetrahydrofuran, was added to the reaction system and dissolved.

[0051] (2) Based on the ammonium hydrolysis product, add vinyl magnesium bromide solution dropwise at a molar ratio of 1:3 for a time of not less than 30 min. After the addition is complete, restore the temperature to room temperature and react for not less than 2 hours to obtain the alkenylated product, racemic (4S*,5R*)-5-((tert-butyldimethylsilyl)oxy)-1,6-heptadien-3-one.

[0052] More preferably, the hydroxyl deprotection reaction equation and steps are as follows:

[0053]

[0054] The alkenylation product, tetrahydrofuran, and triethylamine hydrogen fluoride were added to the reaction system, and the mixture was stirred at 40°C for 12 h. The molar ratio of the alkenylation product to triethylamine hydrogen fluoride was 1:5, yielding the deprotected hydroxyl product, racemic (4R*,5S*)-5-hydroxy-1,6-heptadien-3-one.

[0055] More preferably, the reduction reaction equation and steps are as follows:

[0056]

[0057] (1) Add the hydroxyl deprotection product, tetrahydrofuran, to the reaction system, dissolve it, and cool it to no higher than -78℃;

[0058] (2) Based on the aldol condensation product, add DIBAL-H solution dropwise at a molar ratio of 1:2.7 for a time of not less than 60 min. After the addition is complete, the reaction should be carried out for not less than 5 h to obtain the reduced product, meso (3R*,4R*,5S*)-1,6-heptadien-3,5-diol.

[0059] The (1R,2S,3R)-1-((R)-epoxyethylene-2-yl)-4-penten-1,3-diol compound synthesized according to the aforementioned steps can be used to synthesize polyhydroxy compounds.

[0060] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: 1. It achieves selective oxidation of racemic compounds, using symmetrical, racemic raw materials for unilateral selective oxidation to obtain desymmetric products; 2. It has good functional group derivatization properties, and hydroxyl and epoxy groups can be further converted into pentaneous nucleosides and hexose compounds, which can be used to construct molecules with special stereostructures; 3. It has good catalytic effect, and a small amount of catalyst is sufficient to obtain the target product with excellent results; 4. This method can be carried out at room temperature in an open system, and the operation is simple. Attached Figure Description

[0061] Figure 1 This is a chiral ELSD comparison diagram of the product (1R,2S,3R)-2-methyl-1-((R)-epoxyethylene-2-yl)pent-4-ene-1,3-diol in the embodiments of the present invention.

[0062] Figure 2 This is a chiral HPLC comparison chromatogram of the product (1R,2S,3R)-1-((R)-ethylene oxide-2-yl)-2-phenyl-4-pentene-1,3-diol in the embodiments of the present invention.

[0063] Figure 3 This is a chiral HPLC comparison diagram of the product (1S,2S,3R)-2-(benzyloxy)-1-((R)-epoxy-2-yl)pent-4-ene-1,3-diol in the embodiments of the present invention.

[0064] Figure 4 This is a chiral HPLC comparison diagram of the product (1R,2S,3R)-1-((R)-ethylene oxide-2-yl)-2-phenylethyl-4-pentene-1,3-diol in the embodiments of the present invention.

[0065] Figure 5This is a chiral HPLC comparison diagram of the product (1R,2S,3R)-2-(4-(benzyloxy)butyl)-1-((R)-ethylene oxide-2-yl)pent-4-ene-1,3-diol in the embodiments of the present invention.

[0066] Figure 6 This is a chiral HPLC comparison diagram of the product (1R,2S,3R)-2-(2-fluorophenyl)-1-((R)-epoxyethylene-2-yl)pent-4-ene-1,3-diol in the embodiments of the present invention.

[0067] Figure 7 This is a chiral HPLC comparison chromatogram of the product (1R,2S,3R)-1-((R)-ethylene oxide-2-yl)-2-(p-tolyl)pent-4-ene-1,3-diol in the embodiments of the present invention.

[0068] Figure 8 This is a general diagram of the synthetic route for the target product of this invention. Detailed Implementation

[0069] The technical solution of the present invention will be further described below with reference to the accompanying drawings. Unless otherwise stated, all materials used in the following embodiments are commercially available analytical grade and are used directly without purification.

[0070] Example 1: Synthesis and Screening of Reaction Conditions for Meso-Raceous (3R*,4R*,5S*)-1,6-Heptadien-3,5-Diol Compounds from Starting Materials

[0071] 1.1 Synthesis of raw materials. Intermediate compound 1 was synthesized; the reaction equation is as follows:

[0072]

[0073] General Step A: Weigh 1.0 equiv (19.6 mmol) of substituted ethyl acetate, activated... 1 g of molecular sieve was added to a reaction flask containing dichloromethane (35 mL), and then placed at -78 °C. n-BuBOTf (Dibutylboryltrifluoromethanesulfonate, CAS 60669-69-4, 1.3 equiv, 25.5 mmol) was slowly added dropwise for 30 min, followed by DIEA (Diisopropylethylamine 1.6 equiv, 31.3 mmol) for 30 min. The reaction was stirred for 3.5 h. Finally, freshly distilled acrolein (5.0 equiv, 98 mmol) was added dropwise for 30 min, and the reaction was continued at this temperature with stirring for 2 h. The mixture was then transferred to an ice bath and stirred overnight. After the reaction was complete, water and MeOH:H2O2 (1:1) were added sequentially to quench the reaction. The mixture was then purified by column chromatography (25% PE / EtOAc) to obtain a pale yellow or colorless oily substance (±)-1, a racemic (2R*,3S*)-3-hydroxy-4-pentenoic acid ethyl ester compound, with a yield of 65-95%.

[0074] The reaction equation for the synthesis of intermediate compound 2 is as follows:

[0075]

[0076] General Step B: Weigh compound (±)-1 (1.0 equiv) and 2,6-dimethylpyridine (1.5 equiv) and dissolve them in dichloromethane. Transfer the reaction flask to -78°C and slowly add TBSOTf (tert-Butyldimethylsilyltriflate, CAS 69739-34-0 1.2 equiv) for 30 min. After returning to room temperature, react for 2 h. After the reaction is complete as monitored by TLC, concentrate the reaction solution under reduced pressure and purify by column chromatography (10% PE / EtOAc) to obtain compound (±)-2, a racemic (2R*,3S*)-3-((tert-butyldimethylsilyl)oxy)-4-pentenoic acid ethyl ester compound, with a yield of 90-98%.

[0077] The reaction equation for the synthesis of intermediate compound 3 is as follows:

[0078]

[0079] General Step C: Take a 100 ml round-bottom flask, dissolve compound (±)-2 (1.0 equiv) in tetrahydrofuran, add dimethylhydroxylamine hydrochloride (1.5 equiv), then place in an ice-water bath, slowly add isopropyl magnesium chloride (2.0 mol / L diethyl ether, 3.0 equiv) for 30 min, restore to room temperature and react for 2 h. After the reaction is complete as monitored by TLC, separate and purify by column chromatography (18% PE / EtOAc) to obtain compound (±)-3, a racemic (2R*,3S*)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methyl-4-pentenamide compound, with a yield of 80-92%.

[0080] The reaction equation for the synthesis of intermediate compound 4 is as follows:

[0081]

[0082] General Step D: Take a 100 ml round-bottom flask, dissolve compound (±)-3 (1.0 equiv) in tetrahydrofuran, then place it in an ice-water bath, slowly add vinyl magnesium bromide (1.0 mol / L in THF, 3.0 equiv) for 30 min, restore to room temperature and react for 2 h. After the reaction is complete as monitored by TLC, separate and purify by column chromatography (8% PE / EtOAc) to give compound (±)-4. The yield of racemic (4R*,5S*)-5-((tert-butyldimethylsilyl)oxy)-1,6-heptadien-3-one compounds is 40-68%.

[0083] The reaction equation for the synthesis of intermediate compound 5 is as follows:

[0084]

[0085] General Step E: Take a 50 ml centrifuge tube containing polytetrafluoroethylene (PTFE), dissolve compound (±)-4 (1.0 equiv) in tetrahydrofuran, add triethylamine hydrogen fluoride (5.0 equiv), stir and react at 40 °C for 12 h. After the reaction is complete as monitored by TLC, quench with NaHCO3, extract with EtOAc, dry with anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound (±)-5, a racemic (4R*,5S*)-5-hydroxy-1,6-heptadien-3-one compound, which can be directly transferred to the next step without further post-treatment.

[0086] The reaction equation for the synthesis of intermediate compound 6 is as follows:

[0087]

[0088] General procedure F: Take a 250 mL round-bottom flask, dissolve compound (±)-5 (1.0 equiv, 10 mmol) in 167 mL tetrahydrofuran, transfer the reaction flask to -78 °C, slowly add DIBAL-H (1.0 mol / L in Hexane, 2.7 equiv, 27 mmol) for 1 h, stir the reaction at this temperature for 5 h, monitor the reaction to complete by TLC, quench with 1 M HCl solution, extract with EtOAc 5 times, dry with anhydrous Na2SO4, and purify by column chromatography (40% PE / EtOAc) to obtain compound (±)-6, a meso-(3R*,4R*,5S*)-1,6-heptadien-3,5-diol compound, with a yield of 50-69%.

[0089] 1.2 Screening of reaction conditions. 4-phenyl-substituted 1,6-heptadien-3,5-diol 6b was used as a template raw material for controlled experiments to screen for optimal reaction conditions. The screening process is shown in Table 1.

[0090] Example 2: Determination of substrate adaptability range.

[0091] Based on the results in Table 1, the substituent suitability range of target compound 7 was determined under optimal reaction conditions. The synthetic reaction equation and operation steps for target compound 7 are as follows:

[0092]

[0093] General procedure G: Take a dry 10 mL Shrek tube and add compound (±)-6 (1.0 equiv, 0.1 mmol), Nitro-Salalen titanium catalyst (2.5 mol%, 0.0025 mmol), (n-Bu)4NHSO4 (2.5 mol%, 0.0025 mmol), and 50% H2O2 (1.5 equiv, 0.15 mmol) dissolved in dichloromethane (0.5 mL). React at room temperature for 48 h. After the reaction is complete as monitored by TLC, the mixture is purified by column chromatography to obtain (1R,2S,3R)-1-((R)-epoxyethylene-2-yl)-4-penten-1,3-diol compound 7. The substrate range is shown in the characterization data. Yield: 70-72%, dr = 3.6:1.

[0094] Table 1: Screening of Template Reaction Conditions

[0095]

[0096] [a] 82% ee; [b] yield is the separation yield; [c] dr = 3.6:1; [d] dr = 2.6:1; [e] dr = 2.4:1; [f] dr = 2.2:1; [g] dr = 6:1.

[0097] Using a Nitro-Salalen titanium catalyst and a 50% H₂O₂ catalytic system, (1R,2S,3R)-1-((R)-ethyleneoxy-2-yl)-4-penten-1,3-diol compounds with high enantioselectivity (76-99% ee) were efficiently synthesized at room temperature. The obtained products contain chiral hydroxyl groups and epoxy alkyl groups, and can be further derivatized to generate more small organic molecule intermediates. The type and ratio of eluents used for separation, and the characterization data of compounds 6-7 are given below.

[0098] 1 H NMR and 13 C NMR

[0099] 6a rac-(3R*,4r,5S*)-4-Methylhepta-1,6-diene-3,5-diol.Colorless oil,64%yield,R f =0.20 (40% EtOAc / PE). 1 H NMR (400MHz, CDCl3) δ5.83 (ddd, J=17.2, 10.6, 5.2Hz, 2H), 5.23 (dt, J=17.3, 1.6Hz, 2H), 5.11 (dt, J=10.6, 1. 6Hz, 2H), 4.40 (ddt, J=4.5, 3.0, 1.6Hz, 2H), 3.29 (s, 2H), 1.65 (qt, J=7.1, 2.8Hz, 1H), 0.85 (d, J=7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ139.47,114.69,76.46,42.20,5.41.

[0100] 6b rac-(3R*,4r,5S*)-4-phenylhepta-1,6-diene-3,5-diol.Colorless oil,54%yield,R f =0.20(40%EtOAc / PE).HMRS(ESI)m / z calculated for C 13 H 16 O2Na([M+Na)) + ):227.1043,Found:227.1043. 1H NMR(400MHz,CDCl3)δ7.39–7.26(m,5H),5.77(ddd,J=17.0,10.4,6.6Hz,2H),5.24(dt,J=17.2,1.4Hz,2H),5.12(dt,J=10.4,1.3Hz,2H),4.67–4.60(m,2H),2.72(t,J=5.3Hz,1H),2.05(s,2H). 13 C NMR(101MHz,CDCl3)δ139.16,139.14,136.31,130.44,128.26,127.24,116.33,74.53,74.49,57.14,57.12.IR(thin film)1450,1437,1419,1407,1392,1380,1333,1273,1088,1049 cm -1 .

[0101] 6c rac-(3R*,4r,5S*)-4-(benzyloxy)hepta-1,6-diene-3,5-diol.Colorless oil,69%yield,R f =0.20(40%EtOAc / PE).HMRS(ESI)m / z calculatedfor C 14 H 18 O3Na([M+Na] + ):257.1148,Found:257.1148. 1 H NMR(400MHz,CDCl3)δ7.33(p,J=4.5Hz,5H),5.94(ddd,J=17.4,10.5,5.8Hz,2H),5.39(dt,J=17.2,1.6Hz,2H),5.24(dt,J=10.5,1.5Hz,2H),4.68(s,2H),4.29(d,J=5.2Hz,2H),3.36(t,J=4.5Hz,1H),2.64(d,J=5.6Hz,2H). 13 C NMR(101MHz,CDCl3)δ137.80,137.63,128.55,128.13,128.12,116.75,84.37,75.41,72.72.IR(thin film)3688,2972,2900,1454,1405,1249,1066,1050,925,879,739,699 cm -1 .

[0102] 6d rac-(3R*,4r,5S*)-4-phenethylhepta-1,6-diene-3,5-diol.Colorless oil,51%yield,R f =0.20(40%EtOAc / PE).HMRS(ESI)m / z calculatedfor C 15 H 20 O2Na([M+Na] + ):255.1356,Found:255.1356. 1 H NMR(400MHz,CDCl3)δ7.31–7.23(m,2H),7.20–7.08(m,3H),5.91(ddd,J=17.2,10.6,5.1Hz,2H),5.30(dt,J=17.2,1.7Hz,2H),5.18(dt,J=10.5,1.6Hz,2H),4.49(ddd,J=5.0,3.0,1.6Hz,2H),3.01(d,J=8.7Hz,2H),2.69–2.59(m,2H),1.79–1.71(m,2H),1.68(tt,J=5.5,2.8Hz,1H). 13 C NMR(101MHz,CDCl3)δ142.41,139.60,128.44,128.25,125.75,114.74,75.96,47.02,35.73,24.29.IR(thin film)1496,1453,1142,1032,995,922,750,699 cm -1 .

[0103] 6e rac-(3R*,4r,5S*)-4-(4-(benzyloxy)butyl)hepta-1,6-diene-3,5-diol.Colorless oil,51%yield,R f =0.20(40%EtOAc / PE).HMRS(ESI)m / zcalculated forC 18 H 26 O3Na([M+Na] + ):313.1774,Found:313.1774. 1H NMR(400MHz,CDCl3)δ7.37–7.26(m,5H),5.93(ddd,J=17.3,10.6,5.2Hz,2H),5.28(dt,J=17.2,1.6Hz,2H),5.15(dt,J=10.6,1.6Hz,2H),4.55–4.37(m,2H),3.44(t,J=6.6Hz,2H),2.60(s,2H),1.59(dt,J=13.4,5.0Hz,3H),1.47–1.33(m,4H). 13 C NMR(101MHz,CDCl3)δ139.67,138.57,128.33,127.63,127.49,114.68,75.83,72.86,70.19,48.04,29.98,26.25,22.29.IR(thinfilm)2949,2834,1452,1032,640 cm -1 .

[0104] 6f rac-(3R*,4r,5S*)-4-(2-fluorophenyl)hepta-1,6-diene-3,5-diol.Colorless oil,45%yield,R f =0.20(40%EtOAc / PE);HMRS(ESI)m / z calculatedfor C 13 H 15 O2FNa([M+Na] + ):245.0948,Found:245.0948. 1 H NMR(400MHz,CDCl3)δ7.66(td,J=7.5,1.8Hz,1H),7.22(tdd,J=7.4,5.3,1.9Hz,1H),7.11(td,J=7.6,1.3Hz,1H),7.02(ddd,J=9.7,8.1,1.3Hz,1H),5.78(ddd,J=16.9,10.4,6.1Hz,2H),5.21(dt,J=17.1,1.4Hz,2H),5.09(dt,J=10.5,1.4Hz,2H),4.69(t,J=5.5Hz,2H),3.28(t,J=4.9Hz,1H),2.44(s,2H). 13C NMR(101MHz,CDCl3)δ162.80,160.37,138.74,131.16,131.13,128.47,128.38,123.77,123.74,123.68,123.54,116.15,115.19,114.95,74.60,47.07.IR(thinfilm)2796,1604,1490,1454,1229,1176,1098,1017,927,758cm -1 .

[0105] 6g rac-(3R*,4r,5S*)-4-(p-tolyl)hepta-1,6-diene-3,5-diol.Colorless oil,41%yield,R f =0.20(40%EtOAc / PE);HMRS(ESI)m / z calculatedfor C 14 H 18 O2Na([M+Na] + ):241.1199,Found:241.1199. 1 H NMR(400MHz,CDCl3)δ7.34–7.17(m,2H),7.14(d,J=7.6Hz,2H),5.77(ddd,J=17.1,10.4,6.6Hz,2H),5.25(dt,J=17.2,1.4Hz,2H),5.14–4.99(m,2H),4.62(t,J=6.1Hz,2H),2.70(t,J=5.4Hz,1H),2.33(s,3H),1.93(d,J=3.2Hz,2H). 13 C NMR(101MHz,CDCl3)δ139.22,136.87,132.95,130.24,129.10,116.33,74.43,56.77,21.08.IR(thin film)2972,1615,1372,1053,1032,1016 cm -1 .

[0106] 7a(1R,2S,3R)-2-methyl-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Yellow oil,72%yield,dr=2.4:1,R f=0.20(50%EtOAc / PE).76%ee,HPLCanalysis:IA(n-hexane / 2-propanol=88 / 12,1.0mL / min,ELSD),t(major)8.94min,t(minor)2.82min;HRMS(ESI)m / z calculated for C8H14O3Na([M+Na]+):181.0835,Found:181.0835; 1 H NMR(400MHz,CDCl3)δ5.75(ddd,J=17.0,10.4,7.5Hz,1H),5.31–5.12(m,2H),4.54(td,J=7.4,1.2Hz,1H),3.83–3.62(m,4H),2.25(td,J=7.2,6.0Hz,1H),0.94(d,J=7.3Hz,3H). 13 C NMR(101MHz,CDCl3)δ135.57,117.45,84.61,82.02,78.17,62.68,44.99,12.68,1.01.IR(thinfilm)2948,2834,1660,1453,1370,114,1032,1020,691 cm -1 .

[0107] 7b(1R,2S,3R)-1-((R)-oxiran-2-yl)-2-phenylpent-4-ene-1,3-diol.Colorless oil,78%yield,dr=3.6:1,Rf=0.20(50%EtOAc / PE).82%ee,HPLCanalysis:IM-3(n-hexane / 2-propanol=83 / 17,1.0mL / min,210nm),t(major)7.56min,t(minor)12.25min;HRMS(ESI)m / z calculated for C 13 H 16 O3Na([M+Na] + ):243.0992,Found:243.0992; 1H NMR(400MHz,CDCl3)δ7.36–7.29(m,2H),7.26–7.17(m,3H),5.43(ddd,J=17.2,10.4,6.9Hz,1H),5.16(dt,J=17.1,1.6Hz,1H),4.99(dt,J=10.5,1.4Hz,1H),4.78(td,J=7.7,7.1,1.4Hz,1H),4.51(t,J=7.1Hz,1H),4.04–3.81(m,3H),3.51(t,J=7.7Hz,1H),2.11(s,1H),2.00(s,1H). 13 C NMR(101MHz,CDCl3)δ135.79,128.89,128.47,126.99,117.34,83.96,82.20,62.38,57.36.IR(thin film)2948,28354,1660,1453,1370,1114,1032,1020,691 cm -1 .

[0108] 7c(1S,2S,3R)-2-(benzyloxy)-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Colorless oil,80%yield,dr=5.7:1,Rf=0.20(50%EtOAc / PE).99%ee,HPLC analysis:IM-3(n-hexane / 2-propanol=88 / 12,1.0mL / min,209nm),t(major)10.87min,t(minor)15.90min;HRMS(ESI)m / z calculated for C 14 H 18 O4Na([M+Na]+):273.1097,Found:273.1097; 1H NMR(400MHz,CDCl3)δ7.39–7.26(m,5H),6.04(ddd,J=17.5,10.4,7.5Hz,2H),5.40(ddd,J=17.3,1.7,1.0Hz,1H),5.31(ddd,J=10.4,1.7,0.9Hz,1H),4.64–4.54(m,2H),4.51(dd,J=7.3,4.6Hz,1H),4.30(dd,J=4.1,2.5Hz,1H),3.87(td,J=5.0,4.4,3.2Hz,2H),3.82(dd,J=11.7,3.4Hz,1H),3.78–3.68(m,1H),2.23(s,1H),2.01(s,1H). 13 C NMR(101MHz,CDCl3)δ137.49,133.38,128.47,127.90,127.64,119.08,86.14,84.94,81.89,76.44,72.01,62.72.IR(thin film)2949,2843,1365,1142,1054,1032,1017cm -1 .

[0109] 7d(1R,2S,3R)-1-((R)-oxiran-2-yl)-2-phenethylpent-4-ene-1,3-diol.Colorless oil,68%yield,dr=2.6:1,Rf=0.20(50%EtOAc / PE).HPLCanalysis:IM-3(n-hexane / 2-propanol=88 / 12,1.0mL / min,209nm),t(major)10.27min,t(minor)16.20min;HRMS(ESI)m / z calculated for C 15 H 20 O3Na([M+Na]+):271.1305,Found:271.1305; 1H NMR(400MHz,CDCl3)δ7.31–7.23(m,2H),7.22–7.12(m,3H),5.79(ddd,J=17.1,10.3,8.0Hz,1H),5.29(dt,J=17.1,1.3Hz,1H),5.22(dt,J=10.3,1.2Hz,1H),4.59(t,J=7.9Hz,1H),3.94(t,J=7.0Hz,1H),3.86–3.78(m,1H),3.72(dd,J=9.1,4.6Hz,2H),2.66(t,J=8.0Hz,2H),2.23(p,J=7.6Hz,1H),1.82–1.61(m,2H). 13 C NMR(101MHz,CDCl3)δ141.83,135.46,128.44,128.33,125.97,118.04,84.06,81.73,76.25,62.40,49.55,33.76,29.81.IR(thin film)2949,2834,1652,1453,1371,1114,1032,1018,657 cm -1 .

[0110] 7e(1R,2S,3R)-2-(4-(benzyloxy)butyl)-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Colorless oil,44%yield,dr=2.0:1,Rf=0.20(50%EtOAc / PE).86%ee,HPLC analysis:IA(n-hexane / 2-propanol=91 / 9,1.0mL / min,210nm),t(major)18.31min,t(minor)29.95min;HRMS(ESI)m / z calculated for C 18 H 26 O3Na([M+Na]+):329.1723,Found:329.1723; 1H NMR(400MHz,CDCl3)δ7.40–7.26(m,5H),5.75(ddd,J=17.0,10.3,7.8Hz,1H),5.24(dt,J=17.1,1.3Hz,1H),5.17(dt,J=9.6,1.0Hz,1H),4.55(t,J=7.8Hz,1H),4.49(d,J=3.3Hz,2H),3.86(t,J=6.8Hz,1H),3.83–3.75(m,1H),3.70(dq,J=7.6,4.1Hz,2H),3.46(t,J=6.3Hz,2H),2.36(s,1H),2.16(p,J=6.9Hz,2H),1.76(s,1H),1.61(p,J=6.7,6.3Hz,2H),1.50–1.33(m,4H). 13 C NMR(101MHz,CDCl3)δ138.41,135.55,128.36,127.67,127.57,117.67,84.14,81.80,76.34,72.90,70.10,62.55,50.18,29.70,27.58,24.24.IR(thin film)2831,1770,1616,1365,1268,1148,1057,1033,859,775 cm -1 .

[0111] 7f(1R,2S,3R)-2-(2-fluorophenyl)-1-((R)-oxiran-2-yl)pent-4-ene-1,3-diol.Colorless oil,76%yield,dr=2.5:1,Rf=0.20(50%EtOAc / PE).91%ee,HPLC analysis:IM-3(n-hexane / 2-propanol=91 / 9,1.0mL / min,209nm),t(major)11.76min,t(minor)17.83min;HRMS(ESI)m / z calculated for C 13 H 15 FO3Na([M+Na]+):261.0897,Found:261.0897; 1H NMR(400MHz,CDCl3)δ7.35–7.18(m,2H),7.11(t,J=7.5Hz,1H),7.06–6.96(m,1H),5.41(ddd,J=17.3,10.3,7.3Hz,1H),5.16(d,J=17.0Hz,1H),4.96(dd,J=10.3,1.5Hz,1H),4.88(t,J=7.9Hz,1H),4.60(t,J=7.5Hz,1H),4.01–3.77(m,3H),2.09(s,1H),1.97(s,1H). 13 C NMR(101MHz,CDCl3)δ135.41,128.92,128.88,128.63,128.55,124.12,124.09,117.70,115.45,115.22,83.59,81.20,81.19,74.57,62.13,49.90.IR(thin film)2965,2924,1748,1603,1492,1371,1261,1032,799,755 cm -1 .

[0112] 7g(1R,2S,3R)-1-((R)-oxiran-2-yl)-2-(p-tolyl)pent-4-ene-1,3-diol.Colorless oil,78%yield,dr=2.8:1,R f =0.20(50%EtOAc / PE).88%ee,HPLCanalysis:IM-3(n-hexane / 2-propanol=90 / 10,1.0mL / min,206nm),t(major)14.08min,t(minor)25.95min;HRMS(ESI)m / z calculated for C 14 H 18 O3Na([M+Na]+):257.1148,Found:257.1147; 1H NMR(400MHz,CDCl3)δ7.09(q,J=8.1Hz,4H),5.45(ddd,J=17.2,10.4,6.9Hz,1H),5.15(dt,J=17.1,1.5Hz,1H),5.00(dt,J=10.4,1.4Hz,1H),4.79–4.67(m,1H),4.46(t,J=7.1Hz,1H),4.01–3.77(m,3H),3.47(t,J=7.8Hz,1H),2.13(s,1H),2.02(s,1H). 13 CNMR(101MHz,CDCl3)δ136.61,135.94,134.51,129.18,128.77,117.26,83.87,82.18,62.40,56.92,21.04.IR(thin film)2968,1748,1367,1261,1032,951,801 cm -1 .

Claims

1. A process for the asymmetric synthesis of (1R,2S,3R)-1-((R)-oxan-2-yl)-4- penten-1,3-diol, characterized in that, The 1,6-heptadiene-3,5-diol compound substituted at the fourth position as a raw material, a peroxide as an oxidant, a catalytic oxidation reaction is carried out at room temperature in an organic solvent, the structure general formula of the raw material is: n=0, 1, 2, 3, R=Me, Ph, OBn, o-F-Ph or p-Me-Ph, the organic solvent is one or more combinations of dichloromethane, 1,2-dichloroethane, chloroform; the catalyst of the catalytic oxidation reaction is one or a combination of Berkessel-Katsuki, Nitro-Salalen-Ti, the co-catalyst is one or more combinations of n-butyl hydrogen sulfate, benzoic acid, 2,6-di-tert-butylpyridine, the molar ratio of the raw material, catalyst, peroxide is 1:0.01~0.06:1.0~2.0, the amount of co-catalyst and catalyst is the same, the structure of the Berkessel-Katsuki, Nitro-Salalen-Ti catalyst is respectively: 。 2. The process for the asymmetric synthesis of (1R,2S,3R)-1-((R)-oxan-2-yl)-4- penten-1,3-diol according to claim 1, characterized in that, The molar ratio of the raw material, the catalyst and the peroxide is 1:0.015-0.025:1.2-1.5, and the peroxide is a hydrogen peroxide aqueous solution with a mass fraction of 30-60%.

3. The process for the asymmetric synthesis of (1R,2S,3R)-1-((R)-oxan-2-yl)-4- penten-1,3-diol according to claim 2, characterized in that, The peroxide is a hydrogen peroxide aqueous solution with a mass fraction of 40-55%.

4. The process for the asymmetric synthesis of (1R,2S,3R)-1-((R)-oxan-2-yl)-4- penten-1,3-diol according to claim 1, characterized in that, The duration of the catalytic oxidation reaction is not less than 45 hours.

5. The process for the asymmetric synthesis of (1R,2S,3R)-1-((R)-oxan-2-yl)-4- penten-1,3-diol according to claim 1, characterized in that, The raw material is prepared by subjecting propenal and methyl hydrogen-substituted ethyl acetate to aldol condensation, hydroxyl protection, ammonolysis, Grignard alkenylation, deprotection and reduction in sequence.

6. The process for the asymmetric synthesis of (1R,2S,3R)-1-((R)-oxan-2-yl)-4- penten-1,3-diol according to claim 1, characterized in that, The room temperature is 10-30 DEG C.

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